Rare germline variants in PALB2 and BRCA2 in familial and sporadic chordoma

Bing Xia, Kajal Biswas, Tzeh K. Foo, Thiago T. Gomes, Maximilian Riedel-Topper, Eileen Southon, Zhihua Kang, Yanying Huo, Susan Reid, Stacey Stauffer, Weiyin Zhou, Bin Zhu, Hela Koka, Sally Yepes, Seth A. Brodie, Kristine Jones, Aurelie Vogt, Brian Carter, Neal D. Freedman, Belynda HicksMeredith Yeager, Stephen J. Chanock, Fergus Couch, Dilys M. Parry, Alvaro N. Monteiro, Alisa M. Goldstein, Marcelo A. Carvalho, Shyam K. Sharan, Xiaohong R. Yang

Research output: Contribution to journalArticlepeer-review


Chordoma is a rare bone tumor with genetic risk factors largely unknown. We conducted a whole-exome sequencing (WES) analysis of germline DNA from 19 familial chordoma cases in five pedigrees and 137 sporadic chordoma patients and identified 17 rare germline variants in PALB2 and BRCA2, whose products play essential roles in homologous recombination (HR) and tumor suppression. One PALB2 variant showed disease cosegregation in a family with four affected people or obligate gene carrier. Chordoma cases had a significantly increased burden of rare variants in both genes when compared to population-based controls. Four of the six PALB2 variants identified from chordoma patients modestly affected HR function and three of the 11 BRCA2 variants caused loss of function in experimental assays. These results, together with previous reports of abnormal morphology and Brachyury expression of the notochord in Palb2 knockout mouse embryos and genomic signatures associated with HR defect and HR gene mutations in advanced chordomas, suggest that germline mutations in PALB2 and BRCA2 may increase chordoma susceptibility. Our data shed light on the etiology of chordoma and support the previous finding that PARP-1 inhibitors may be a potential therapy for some chordoma patients.

Original languageEnglish (US)
Pages (from-to)1396-1407
Number of pages12
JournalHuman mutation
Issue number10
StatePublished - Oct 1 2022


  • BRCA2
  • PALB2
  • chordoma
  • genetic susceptibility
  • rare germline variants

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Rare germline variants in PALB2 and BRCA2 in familial and sporadic chordoma'. Together they form a unique fingerprint.

Cite this